The low rate of severe toxicities was noteworthy in both studies: Grade 3 or 4 myelosuppression was seen in 13% of the relapsed/refractory patients and 6% of the treatment naive group in one study; grade 3 or 4 infections were seen in 40% of the relapsed/refractory group and 10% of the previously untreated patients in the other study.

The findings, which essentially confirm early-stage studies reported last year, suggest that ibrutinib could quickly become the standard of care for CLL if ongoing and planned phase III trials show similar results, according to presentations at the American Society of Hematology annual meeting.

In one study involving 116 patients with previously untreated or relapsed or refractory CLL, almost 70% showed objective responses, reported John Byrd, MD, of Ohio State University in Columbus.

Progression-free survival (PFS) after 22 months in the trial was 96% among the treatment-naive patients and 76% in those who had failed or relapsed on previous conventional therapies.

The other trial, reported by Jan Burger, MD, PhD, of MD Anderson Cancer Center in Houston, yielded an objective response rate of 83% in patients with high-risk CLL treated with daily oral ibrutinib and periodic infusions of rituximab (Rituxan).

At an ASH press briefing on these studies, moderator Claire Dearden, MD, of the Royal Marsden NHS Foundation Trust in London, called the findings "hugely exciting for us as clinicians but also for patients."

BTK has recently emerged as a target in CLL because of its role in B-cell antigen receptor signaling, which appears to be critical in the abnormal hematopoietic activity that drives CLL and certain other disorders.

Ibrutinib, which was previously called PCI-32765, is the most advanced of several investigational compounds targeting BTK.

Burger said that ibrutinib was now being tested in phase III trials that would determine whether the drug is really as effective and safe as the current data indicate.

His study involved 91 patients with poor-prognosis CLL, defined as poor responses to previous therapies or the presence of genomic factors associated with resistance to current treatments and early mortality. These include 17p and 11q deletions and unmutated immunoglobulin heavy chain sequences.

Patients received 420 mg/day of ibrutinib along with weekly infusions of rituximab during the first month followed by monthly infusions through month 6.

One patient showed a complete response and 32 had partial responses, for an overall objective response rate of 83%.

Another three patients (8%) had partial responses with residual lymphocytosis, two (5%) had no response, and two have not been in the study long enough to evaluate, Burger said.

Byrd's study used ibrutinib at 420 mg/day as monotherapy, with median follow-up of 22 months. He presented results separately for the 31 previously untreated patients versus the 85 with relapsed or refractory disease:

In the previously untreated patients, rates of both PFS and overall survival (OS) stood at 96% after 22 months. For the relapsed/refractory patients, 22-month PFS was 76% and OS was 85%.

Byrd noted that PFS was not as good in the subset of patients with 17p deletions, but at 55% it was still far superior than would be expected with current therapies.

Noteworthy in both studies was the low rate of severe toxicities, Byrd and Burger said. Grade 3 or 4 myelosuppression was seen only in 13% of the relapsed/refractory patients and 6% of the treatment naive group in Byrd's monotherapy study, and was similarly rare with the combination regimen reported by Burger.

Grade 3 or 4 infections occurred in 10% of the previously untreated patients and 40% of the relapsed/refractory group in Byrd's study. Burger said one patient in his study died after developing fungal and bacterial pneumonia with intracranial abscesses.

Diarrhea, almost entirely grade 1 or 2, was the most common side effect in both trials. Others included myalgia and bone pain, bruising, nausea, and fatigue.

Dearden said that, on the strength of the results presented here, clinicians and patients would eagerly await ibrutinib's wider availability.

"It's orally active, it's well tolerated, it's not chemo, and it produces excellent responses, particularly in patients who are elderly and frail and not necessarily suitable for the more intensive chemotherapy regimens that have become the first-line treatment for the younger, fitter patients," she said.

"There's a lot of excitement about the possibility of the landscape changing, and of moving towards having chemo-free treatments for patients with CLL that are as effective as giving them chemotherapy agents," she added.

Both studies were funded by Pharmacyclics, which is developing ibrutinib.

Study authors reported relationships with Pharmacyclics, Celgene, Portola, Calistoga, Genzyme and Onyx. Some co-authors of both studies are Pharmacyclics employees.

Dearden reported relationships with Roche and Genzyme.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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